HOXA9 Cooperates with Activated JAK/STAT Signaling to Drive Leukemia Development

Cancer Discovery
C E de BockJ Cools

Abstract

Leukemia is caused by the accumulation of multiple genomic lesions in hematopoietic precursor cells. However, how these events cooperate during oncogenic transformation remains poorly understood. We studied the cooperation between activated JAK3/STAT5 signaling and HOXA9 overexpression, two events identified as significantly co-occurring in T-cell acute lymphoblastic leukemia. Expression of mutant JAK3 and HOXA9 led to a rapid development of leukemia originating from multipotent or lymphoid-committed progenitors, with a significant decrease in disease latency compared with JAK3 or HOXA9 alone. Integrated RNA sequencing, chromatin immunoprecipitation sequencing, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) revealed that STAT5 and HOXA9 have co-occupancy across the genome, resulting in enhanced STAT5 transcriptional activity and ectopic activation of FOS/JUN (AP1). Our data suggest that oncogenic transcription factors such as HOXA9 provide a fertile ground for specific signaling pathways to thrive, explaining why JAK/STAT pathway mutations accumulate in HOXA9-expressing cells.Significance: The mechanism of oncogene cooperation in cancer development remains poorly characterized. In this study, we mode...Continue Reading

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Citations

Jun 25, 2019·ELife·Michael P MeersSteven Henikoff
Dec 21, 2019·Laboratory Medicine·Mohammad ShahjahaniHadi Rezaeeyan
Dec 4, 2019·British Journal of Cancer·Paniz Tavakoli ShiraziDeborah L White
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Jul 16, 2021·ELife·William F RichterAlexander J Ruthenburg
Sep 4, 2021·HemaSphere·Inge LodewijckxJan Cools
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Nov 12, 2021·Blood·Charles E de Bock, Jan Cools
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